This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this proposal is to achieve a deeper understanding of in vivo nitrogen metabolism in human, with specific foci on interactions between essential amino acid metabolism and urea synthesis and on diseases affecting the urea cycle. Our past work has indicated that in comparison with normal individuals, patients with genetic defects in urea synthesis may exhibit a partial block in their ability to utilize gluatmine as a urea nitrogen source. As a consequence they rely more on enterally generated nitrogen as a source of urea. In addition we and others have also shown that a common therapy for such patients, i.e., the ingestions of either phenylbutyrate or phenylacetate, often in combination with benzoate;diverts nitrogen from the urea synthesis to alternative routes of excretion and hence achieves its therapeutic objective. However,our studies suggest that this therapeutic modality has a substantial impact on branched chain amino acid metabolism (BCAA). In fact, this meabolic disruption leads to a marked fall in BCAA concentrations in spite of adequate levels of total protein intake. One predicted outcome of the effect of these druge, is to inhibit body protein synthesis. Uniquely,this clinical scenario may provide an opportunity to selectively evaluate the role of branch chain amino acids in regulating global protein synthesis. Accordingly, we propsoe experiments in normal subjects and in patients suffering from partial and/or severe defects in urea synthesis to test these hypotheses. These findings should directly impact on our nutritional management of these and other disorders in which restriction of protein intake is a main stay of therapy.